Better together – Novel dual-acting and disease-modifying approach to combat Alzheimer’s

Alzheimer‘s disease (AD) is a neurodegenerative disorder with cognitive, functional, and behavioral alterations. AD is progressive and memory loss and personality changes pose a great burden for the more than 25 million patients and their families worldwide. Despite all efforts to identify the cause and halt the fast progression, only 5 drugs are currently approved in the US for treating the cognitive decline with no new therapies in over a decade. The cholinesterase (ChE) inhibitor tacrine raises levels of the neurotransmitter acetylcholine (ACh). However, the compound exhibits dose-dependent hepatotoxicity and acts only symptomatically, like all approved drugs. Due to the complex pathophysiology of AD, multi-target strategies may be the way forward¹. Here, tacrine can pose a promising start for developing a multitarget drug. The last years have yielded evidence that activating the human cannabinoid receptor subtype 2 receptor reduces overall AD-like pathology by attenuating associated neuroinflammation and improving cognitive impairment in animal models².

Here, we present hybrids of tacrine and an hCB2R agonist connected by different linkers. All synthesized hybrids showed pronounced inhibition of human ChEs compared to tacrine alone and interfered with overall β-amyloid aggregation. The most promising hybrids showed pronounced anti-neuroinflammatory effects in vitro on microglia cells and neuroprotection in vivo as evidenced by attenuation of short- and long-term memory in a murine Alzheimer’s model³. Importantly, even high doses of hybrid compounds (3mg/kg) lacked hepatotoxicity seen with tacrine alone.

• Stronger inhibition of ChEs compared to tacrine alone
• Efficient crossing of blood-brain barrier despite high molar mass
• High in vivo efficacy even at low dosages (0.1 mg/kg) and no liver toxicity

Proof of concept in vitro and in vivo Alzheimer’s model.